We have previously shown that chronic activation of mitogenic signaling induced by overexpression of c-myc and transforming growth factor-alpha (TGF-a) transgenes in mouse liver induces a state of oxidative stress. We therefore proposed that increased reactive oxygen species (ROS) generation might be responsible for the extensive chromosomal damage and acceleration of hepatocarcinogenesis characteristic for TGF-a/c-myc mice. In this study we show that Vitamin E (VE), a potent free radical scavenging antioxidant, is able to protect liver tissue against oxidative stress and suppress tumorigenic potential of c-myc oncogene. Dietary supplementation with VE, starting from weaning, decreased ROS generation coincident with a marked inhibition of hepatocyte proliferation while increasing the chromosomal as well as mtDNA stability in the liver. Similarly, dietary VE reduced liver dysplasia and increased viability of hepatocytes. At six months of age, VE treatment decreased the incidence of adenomas by 65% and prevented malignant conversion. These results indicate that ROS generated by overexpression of c-myc and TGF-a in the liver are the primary carcinogenic agents in this animal model. Furthermore, the data demonstrate that dietary supplementation of VE can effectively inhibit liver cancer development. Next, we analyzed the expression of gluthatione peroxidase (GPX1), since there is a strong evidence that GPX1 is a major antioxidant enzyme that protects cells against lethal oxidative stress. We found that both catalytic activity and protein levels of GPX1were significantly (about 5-7 fold) reduced in TGF-a/c-myc tumors. Concomitantly, we observed a frequent loss of one copy of chromosome 9 or its band 9F where a GPX1 gene is located. Further studies are required to determine the possible role of GPX1 as a chemopreventive enzyme in certain types of cancer.